Iloprost is a synthetic prostacyclin analogue. It mimics at least some of the biological activity of prostacyclin (also referred to as PGI2 or epoprostenol) which is known to decrease arterial resistance, inhibit fibroblast growth, reduce platelet aggregation, and believed to be involved in anti-inflammatory and antimitogenic processes. The chemical name of iloprost according to IUPAC is 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]-bi-cyclo[3.3.0]octan-3-ylidene}pentanoic acid, but it is also known as (E)-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-Δ2(1H),Δ-pentalenevaleric acid. More precisely, iloprost refers to the mixture of the 4R and 4S diastereomers at a ratio of approximately 53:47. It is an oily substance and soluble in methanol, ethanol, ethyl acetate, acetone and aqueous buffer at pH 7, sparingly soluble in aqueous buffer pH 9 and very slightly soluble in distilled water and aqueous buffer at pH 3 and pH 5. The molecular formula is C22H32O4, which corresponds to a molecular weight of 360.49.
Iloprost is used in the therapy of pulmonary arterial hypertension, scleroderma, Raynaud's phenomenon and certain types of ischaemia. It is available as an aqueous inhalation solution (Ventavis®, sold by Actelion Pharmaceuticals in the USA and by Bayer Pharma in Europe and some other countries) for the aerosol treatment of pulmonary arterial hypertension. An injectable formulation of iloprost (Ilomedin®), also sold by Bayer Pharma and Actelion, is also used for the treatment of PAH. Ilomedin® is available in the form of 1 mL ampoules with an iloprost concentration of 20 μg/mL. In certain countries, other vial sizes and concentrations appear to be marketed as well.
According to the prescribing information for the US (version issued December 2011), the inactive ingredients in Ventavis® are tromethamine, ethanol, sodium chloride, hydrochloric acid for pH adjustment, and water for injection. The formulation may also be described as comprising iloprost in the form of iloprost tromethamine, i. e. the tromethamine salt of iloprost.
Pulmonary hypertension (PH) is a severe and potentially life-threatening disease characterised by an increase in blood pressure in the pulmonary circulation, typically associated with dizziness, fainting, shortness of breath, and exercise intolerance. Currently, pulmonary hypertension (PH) is classified by the WHO into 5 groups with pulmonary arterial hypertension (PAH) as group I. Pulmonary arterial hypertension may be further differentiated into idiopathic (IPAH) and heritable pulmonary arterial hypertension (HPAH) and other forms, the latter being induced by intake of drugs and toxins or associated with other diseases such as connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, shistosomiasis or chronic haemolytic anaemia.
Prostacyclin and prostacyclin analogues are often considered as the most effective treatment options in particular for severe pulmonary arterial hypertension. Prostacyclin itself, or epoprostenol (Flolan®), is available as an injectable formulation which requires infusion through a central venous catheter. It is highly unstable and has to be cooled even during administration. A synthetic prostacyclin analogue which is more stable is treprostinil (Remodulin®) which can be administered intravenously or subcutaneously; however, subcutaneous injection is typically rather painful. Iloprost, which has a longer elimination half-life, may be administered intravenously (Ilomedin®) or by inhalation (Ventavis®). More recently, an inhalable form of treprostinil (Tyvaso®) was introduced to the market.
Inhalable iloprost (Ventavis®) is marketed in two strengths (10 μg/mL and 20 μg/mL, respectively), and administered from 6 to 9 times per day using the HaloLite® AAD®, the Prodose® AAD® inhaler system, the Venta Neb® or the I-neb® AAD® inhaler system. The Prodose® and HaloLite® inhalers are jet nebulisers which not marketed any more. The Venta Neb® is an ultrasonic nebulizer whereas the I-neb® system, which is the currently recommended inhalation system, is based on the more advanced vibrating mesh nebuliser technology. The administration of a single dose of 2.5 μg of iloprost using the formulation with 10 μg/mL of iloprost and one of the jet nebulisers takes about 4 to 5 minutes, that of a 5.0 μg dose approximately 8 to 10 minutes. The duration of administration is slightly shorter when using the I-neb® system, requiring about 3.2 minutes for the lower dose (2.5 μg) and about 6.5 minutes for the higher dose (5.0 μg), respectively (see Ventavis® 10 Mikrogramm/ml Lösung für einen Vernebler, Fachinformation, Bayer Pharma, July 2011). A single dose of 5 μg may also be administered using the formulation with 20 μg/mL of iloprost (in countries where this formulation is available), which takes approximately 4 minutes to inhale when using the I-neb® AAD® inhaler system. In practice, however, patients often experience longer inhalation times (10 to 15 min) than reported from controlled clinical trials.
In the context of inhalation treatment using Ventavis®, a single dose of 2.5 μg or 5.0 μg is generally understood as the dose of iloprost which is delivered from the inhalation device at the mouthpiece (see Ventavis® 10 Mikrogramm/ml Lösung für einen Vernebler, Fachinformation, Bayer Pharma, July 2011).
Considering the required frequency of administration and the duration of each administration cycle, the use of inhalable iloprost does not appear to be very convenient or patient-friendly.
However, a shorter time of administration through an increased aerosol delivery rate has been considered unfeasible in the past. In fact, when the suitability of an ultrasonic nebuliser having a high output rate for the administration of inhalable iloprost was tested, which could have potentially decreased the administration time significantly, researchers consented that, due to the expectation of serious adverse events, the concentration of iloprost in the inhalation solution had to be decreased so that the treatment remained sufficiently tolerable.
The strong bias against shortening the inhalation time in the case of iloprost is, for example, expressed by Gessler et al., Ultrasonic versus jet nebulization of iloprost in severe pulmonary hypertension, Eur. Respir. J. 17:14-19 (2001). The authors state that on the basis of a comparison of the physical aerosol characteristics of the conventional jet nebuliser and the more efficient ultrasonic nebuliser there would have been the potential that in the case of the ultrasonic nebuliser the inhalation time for delivery of a single dose of 2.8 μg at the mouthpiece could have been reduced from 12 minutes to 2 minutes. However, this was considered to be therapeutically unfeasible, and the rapid inhalation had to be prevented because preliminary right heart catheter investigations had shown that adverse systemic effects (drop in blood pressure, decrease in systemic vascular resistance, flush, jaw pain, etc.) were associated with such rapid inhalation of iloprost. Therefore, the investigators decided to reduce the concentration of the iloprost inhalation solution from 10 μg/mL to 5 μg/mL when using the ultrasonic nebuliser, which resulted in an inhalation time of 4 minutes with this device.
Hence, therapy with inhalable iloprost remains inconvenient and time-consuming for patients. Thus there remains a need for improving the patient-friendliness of iloprost administration via the pulmonary route.
It is an object of the present invention to provide such improved therapy which is more convenient than the conventional treatment. In a further aspect, it is an object of the invention to provide methods, compositions, and kits for administering inhalable iloprost which overcome at least one of the disadvantages known from conventional iloprost aerosol therapy.